The Pseudokinase MLKL and the Kinase RIPK3 Have Distinct Roles in Autoimmune Disease Caused by Loss of Death-Receptor-Induced Apoptosis

• Published in: Immunity (Cambridge, Mass.) Vol. 45; no. 3; pp. 513 - 526
• Main Authors: Alvarez-Diaz, Silvia, Dillon, Christopher P., Lalaoui, Najoua, Tanzer, Maria C., Rodriguez, Diego A., Lin, Ann, Lebois, Marion, Hakem, Razq, Josefsson, Emma C., O’Reilly, Lorraine A., Silke, John, Alexander, Warren S., Green, Douglas R., Strasser, Andreas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.09.2016; Elsevier Limited
• Subjects: Animals; Apoptosis; Apoptosis - physiology; Autoimmune diseases; Autoimmune Diseases - metabolism; Caspase 8 - metabolism; Cell Death - physiology; Cloning; Evacuations & rescues; Fas-Associated Death Domain Protein - metabolism; Gangrene; Immunoglobulins; Kinases; Ligands; Lymphocytes; Medical research; Mice; Mice, Inbred C57BL; Necrosis - metabolism; Protein Kinases - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Statistical analysis; Tumor necrosis factor-TNF
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.07.016

The kinases RIPK1 and RIPK3 and the pseudo-kinase MLKL have been identified as key regulators of the necroptotic cell death pathway, although a role for MLKL within the whole animal has not yet been established. Here, we have shown that MLKL deficiency rescued the embryonic lethality caused by loss of Caspase-8 or FADD. Casp8−/−Mlkl−/− and Fadd−/−Mlkl−/− mice were viable and fertile but rapidly developed severe lymphadenopathy, systemic autoimmune disease, and thrombocytopenia. These morbidities occurred more rapidly and with increased severity in Casp8−/−Mlkl−/− and Fadd−/−Mlkl−/− mice compared to Casp8−/−Ripk3−/− or Fadd−/−Ripk3−/− mice, respectively. These results demonstrate that MLKL is an essential effector of aberrant necroptosis in embryos caused by loss of Caspase-8 or FADD. Furthermore, they suggest that RIPK3 and/or MLKL may exert functions independently of necroptosis. It appears that non-necroptotic functions of RIPK3 contribute to the lymphadenopathy, autoimmunity, and excess cytokine production that occur when FADD or Caspase-8-mediated apoptosis is abrogated. •MLKL is an essential effector of necroptosis in vivo•RIPK3 exacerbates the development and progression of ALPS-like disease•RIPK3 and maybe MLKL exert additional functions beyond inducing cell death Necroptosis is a form of regulated cell death implicated in several pathologies. MLKL was shown to be critical for necroptosis in vitro. Alvarez-Diaz et al. demonstrate that MLKL, like RIPK3, is essential for necroptosis in vivo and reveal that RIPK3 also has a role beyond cell death in promoting lymphadenopathy and autoimmune disease.